Glutamine synthetase (GS) in brain is located mainly in astrocytes. One of the primary roles of astrocytes is to protect neurons against excitotoxicity by taking up excess
ammonia and
glutamate and converting it into
glutamine via the
enzyme GS. Changes in GS expression may reflect changes in astroglial function, which can affect neuronal functions.
Hyperammonemia is an important factor responsible of
hepatic encephalopathy (HE) and causes astroglial swelling.
Hyperammonemia can be experimentally induced and an adaptive astroglial response to high levels of
ammonia and
glutamate seems to occur in long-term studies. In hyperammonemic states, astroglial cells can experience morphological changes that may alter different astrocyte functions, such as
protein synthesis or
neurotransmitters uptake. One of the observed changes is the increase in the GS expression in astrocytes located in glutamatergic areas. The induction of GS expression in these specific areas would balance the increased
ammonia and
glutamate uptake and protect against neuronal degeneration, whereas, decrease of GS expression in non-glutamatergic areas could disrupt the neuron-glial metabolic interactions as a consequence of
hyperammonemia. Induction of GS has been described in astrocytes in response to the action of
glutamate on active
glutamate receptors. The over-stimulation of
glutamate receptors may also favour
nitric oxide (NO) formation by activation of
NO synthase (NOS), and NO has been implicated in the pathogenesis of several
CNS diseases.
Hyperammonemia could induce the formation of inducible NOS in astroglial cells, with the consequent NO formation, deactivation of GS and dawn-regulation of
glutamate uptake. However, in glutamatergic areas, the distribution of both glial
glutamate receptors and glial
glutamate transporters parallels the GS location, suggesting a functional coupling between
glutamate uptake and degradation by
glutamate transporters and GS to attenuate
brain injury in these areas. In
hyperammonemia, the astroglial cells located in proximity to blood-vessels in glutamatergic areas show increased GS
protein content in their perivascular processes. Since
ammonia freely crosses the blood-brain barrier (BBB) and astrocytes are responsible for maintaining the BBB, the presence of GS in the perivascular processes could produce a rapid
glutamine synthesis to be released into blood. It could, therefore, prevent the entry of high amounts of
ammonia from circulation to attenuate neurotoxicity. The changes in the distribution of this critical
enzyme suggests that the
glutamate-
glutamine cycle may be differentially impaired in hyperammonemic states.